6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel d-Amino Acid Oxidase Inhibitors

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• 作者：Niyada Hin ; Bridget Duvall ; Dana Ferraris ; Jesse Alt ; Ajit G. Thomas ; Rana Rais ; Camilo Rojas ; Ying Wu ; Krystyna M. Wozniak ; Barbara S. Slusher ; Takashi Tsukamoto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7258-7272
• 全文大小：491K
• ISSN：1520-4804

文摘

A series of 2-substituted 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione derivatives were synthesized as inhibitors of d-amino acid oxidase (DAAO). Many compounds in this series were found to be potent DAAO inhibitors, with IC₅₀ values in the double-digit nanomolar range. The 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione pharmacophore appears metabolically resistant to O-glucuronidation unlike other structurally related DAAO inhibitors. Among them, 6-hydroxy-2-(naphthalen-1-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione 11h was found to be selective over a number of targets and orally available in mice. Furthermore, oral coadministration of d-serine with 11h enhanced the plasma levels of d-serine in mice compared to the oral administration of d-serine alone, demonstrating its ability to serve as a pharmacoenhancer of d-serine.